Pediatric

Tuberculosis

Craig T. Nakamura, M.D. March 19, 2012

Global Epidemiology of TB

• TB remains leading infectious disease in world – >40% of world’s population (> 2 billion people)

infected with M. tuberculosis – In 1990s:

• 90 million new cases • 30 million deaths

– Among children < 15 y/o: • Aprox 13 million cases • 5 million deaths

Outline

• Epidemiology • Transmission • Pathogenesis • Public Health Aspects & TB Control • Treatment of Latent TB Infection & TB

Disease • BCG Vaccine

US TB Trends (1986-2003)

0

2,000

4,000

6,000

8,000

10,000

86 87 88 89 90 91 92 93 94 95 96 97 98 990102030405060

No. of Cases Percentage of Total Cases

No. of Cases Percentage

00 01 02 03

CDC

TB Cases by Age (US), 2003

25 - 44 yrs

(34%)

<15 yrs

(6%) 15 - 24 yrs

(11%)

45 - 64 yrs (29%)

65+ yrs (20%)

Epidemiology of TB

• Case rates are declining • Foreign born persons account for > 50% of US cases • TB in children:

– Highest risk for disease: • < 5 years of age • Foreign-born children

– 60% of cases develop within 18 mo of arrival in US – Most common countries of birth: Mexico, Philippines, Vietnam – Varies depending on immigration pattern

• Racial ethnic minorities

Transmission of M. tuberculosis

• Spread by airborne route; droplet nuclei • Transmission affected by:

– Infectiousness of patient – Environmental conditions – Duration of exposure

• Most exposed persons don’t become infected

TB Pathogenesis: Latent TB Infection

• Once inhaled, travel to alveoli & establish infection

• After 2 – 12 wks, immune response limits activity; infection detectable

• Some bacteria survive & remain dormant but viable for years = latent TB infection (LTBI)

TB Pathogenesis: LTBI

•Persons with LTBI are: – Asymptomatic – Not infectious

TB Pathogenesis: Active TB

LTBI progresses to TB disease in: • Small number of persons after infection • 5% – 10% of persons with untreated LTBI

sometime during life • 10% in HIV (with untreated LTBI) per year

Factors Increasing TB Spread

• Adolescents / Adults • Cough / Failing to cover cough • Cough-inducing or aerosol-generating

procedure • Positive sputum AFB smear • Cavitation on chest radiograph • Inadequate treatment

Significance of Pediatric TB

A case of TB in a child is a “sentinel healthcare event”

[represents recent transmission]

TB by site: children (< 15 y/o)

Extrapulmonary20%

Pulmonary75%

Pulmonary & Extrapulmonary

5%

Extrapulmonary TB in Children (< 15)

5

636

86

12 MiliaryLymphaticPleuraMeningealBone/JointOther

TB Control in US

• Identification of new cases TB – Initiate appropriate Rx – Directly observed therapy (DOT)

• Contact Investigations – Identify persons at risk

• Targeted tuberculin testing – Identifies persons at high risk who would

benefit from LTBI Rx – Treatment LTBI

AAP Recommendations: Targeted TST

• Exposure risk assessed at clinic visits • Only children with increased risk

considered for testing • Freq of testing depends on degree of risk • “Screening” is inefficient way to control

TB

Targeted TST Risk-Assessment

• Child born outside US? – Africa, Asia, Eastern Europe, Latin

America • Child traveled outside US (> 1 week)? • Child exposed to anyone with TB?

– (TB?; LTBI?; Nature of contact?) • Close contact with a person with (+)

TST? Pediatrics 2004;114:1175, supplement

Targeted TST Risk-Assessment

• Depending on local epidemiology other questions: – Does child spend time with anyone in jail,

shelter, uses illegal drugs, or HIV (+)? – Has child had raw milk or unpasteurized

cheese? – Any household member born outside US? – Any household member travel outside US?

Pediatrics 2004;114:1175, supplement

AAP Recommendations: TST

• Children who should have immediate TST:

– Contacts of persons with confirmed / suspected TB (contact investigation)

– Children with CXR or clinical findings suggesting TB – Children from endemic countries – Children with histories of travel to endemic countries /

contact with persons from those countries

Red Book 2003

AAP Recommendations: TST

• Children who should have annual TST:

– HIV infection – Incarcerated adolescents

Red Book 2003

AAP Recommendations: TST

• Consider testing children every 2 - 3 years if: – Exposed to:

• HIV-infected • Homeless • Residents of nursing homes • Institutionalized / incarcerated persons • Users of illicit drugs • Migrant farm workers

– Foster children with exposure to adults in high risk groups

AAP Recommendations: TST

• Consider TST at 4-6 and 11-16 years of age if:

– Parents immigrated (? TST status) from regions with high prevalence

– Continued exposure by travel to or exposure

to contacts from endemic areas (? TST status)

Administering TST

• Inject intradermally 0.1 ml of 5 TU PPD tuberculin

• Wheal 6 mm – 10 mm diameter

• Placed & read by experienced health professionals

Reading the TST

• Read reaction 48 - 72 hours after

• Measure only induration

• Record in millimeters

Parental Reading TST

• TST was placed; 37 children different families – Parents were instructed verbally about:

• Importance • When & how to read induration

– Written instructions – Date stamped on hands

– Site marked with marker & bracelet with reading date placed on child

• Results: 36 / 37 returned for reading – Only 22% of families (8/36) able to both read & document

TST results appropriately

Cheng TL, PIDJ 1996

TST

• Most used test for M. tuberculosis infection in US

• Use recommended Mantoux method – Training materials available from CDC website: http://www.cdc.gov/nchstp/tb/pubs/pem.htm – Multipuncture (e.g., tine) tests not as reliable

– Contact HD for additional TST resources

Special Considerations in TST

• Anergy • Antiretroviral therapy for HIV infection • Pregnancy • TST boosting • Use of two-step TST • BCG vaccination • Differences in PPD preparations

Different PPD Preparations

• Two PPD preparations available in U.S. – APLISOL®

– Tubersol® • Compared to U.S. standard, no differences*

* Villarino ME, Burman W, Wang YC, Lundergan L, Catanzaro A, Bock N, Jones C, Nolan C. Comparable specificity of 2 commercial tuberculin

reagents in persons at low risk for tuberculosis infection. JAMA 1999:281(2):169-71.

(+) TST in Children: Definitions

• Takes into account:

– Risk of infection (exposure) – Risk of progression to disease

• Immune status • Age

Positive TST Results: Infants, Children, & Adolescents

• TST (+) if > 5 mm induration when: – Close contact with known / suspected

contagious cases TB – Suspected TB disease:

• CXR consistent with active / previously active TB • Clinical evidence TB

– Immunosuppressive therapy – Immunosuppressive conditions – HIV infection

Positive TST Results: Infants, Children, & Adolescents

• TST (+) if > 10 mm induration in children when: – Increased risk of disseminated disease:

• Young age (< 4 y/o) • Certain medical conditions (Hodgkin disease, lymphoma,

diabetes mellitus, chronic renal failure, malnutrition) – Increased exposure to TB

• Born / parents born or travel to high-prevalence regions • Frequently exposed to high-risk adults (HIV, homeless,

illicit drug users, nursing homes residents, incarcerated/ institutionalized, migrant farm workers)

Positive TST Results: Infants, Children, and Adolescents

• TST considered (+) when > 15 mm induration • If TST ≥ 15 mm [even up to 7 days after

placement, considered (+)]

Interpreting TST Result

• Probability of (+) TST accuracy depends on M. tuberculosis prevalence in community

low prevalence = low probability of accuracy

high prevalence = high probability of accuracy

Interpreting TST Result

Cut points depend on: • Patient’s risk for having LTBI • Size of induration

>5 mm highest risk

>10 mm other risk factors

>15 mm no known risk factors

Evaluating Child with (+) TST

• Evaluation of children with (+) TST: – Careful history – Household investigation – Physical exam – CXRs (PA & lateral)

Treatment LTBI in Children

• INH 10 mg/kg (max: 300 mg) po qDay x 270 doses • Alternative: Twice weekly directly observed (DOT) INH

20 - 40 mg/kg (max: 900 mg) po x 72 doses • Monitor index case isolate sensitivities • Hepatotoxicity from INH is rare in children:

– Monthly assessment for clinical evidence: decreased appetite or weight, nausea, vomiting, abdominal pain, jaundice

– Routine LFTs NOT indicated

TB Control in US

• Contact Investigations “The most reliable TB control program is

based upon aggressive & expedient contact investigations, rather than routine screening of large populations with low risk.”

Complex, requires experience, & lots of

work.

Work-up Exposure in Children

• History, physical exam, TST, CXR • Ok if > 4 y/o and:

– Asymptomatic with normal physical exam – TST is neg – Chest X-ray normal

• But if < 4 yo, start: INH 10 mg/kg (max., 300 mg) po qDay

TB Exposure in Children

• Why INH if no evidence infection at initial visit?: – May already be infected – Infection more likely to progress to

disease – Infants & younger children are more likely

to have disseminated disease (or meningitis)

• Repeat TST 12 wks after contact broken: – If TST (-), d/c INH – If TST (+), re-evaluate child & treat

accordingly

Missed Opportunities

• Failure to find & manage source cases • Delay in reporting initial dx • Contact interview failure • Delay in evaluating exposed children • Failure to completely evaluate exposed children • Failure to maintain surveillance • LTBI diagnosed; Rx not prescribed • Failure to complete treatment for LTBI (adherence)

Importance of Pediatric Radiologic Expertise

• Many pitfalls: – Occasional poor quality films – Repeat CXR at the same institution, may

not address the questions on initial films – Negative CXRs read positive – Positive CXRs read as normal

BCG Vaccine & TST

• Hx of BCG is NEVER contraindication to TST • Can’t distinguish + TSTs of BCG from infection with M.

tuberculosis • Therefore, management of children with a history of

BCG & + PPD: – History – CXR – Appropriate Rx

BCG – Fantasy vs Fact

FANTASY FACT

• BCG protects against getting TB infection • BCG will not protect against becoming infected with TB

• BCG provides lifetime protection against developing active TB

• BCG Protects against severe complications of TB disease in young children. Provides little or no protection in adolescents and adults

• BCG causes the tuberculin skin test (TST) to be positive for life

• BCG causes the TST pos for a few years & then TST reaction becomes much weaker. Generally, no reaction is present after 5 years.

• In a BCG-vaccinated person, a pos TST is most likely due to BCG

• There is no way to tell whether a pos TST is due to BCG or TB infection

• A positive TST in a person of any age from any country is most likely due to BCG, not TB infection

• A pos TST in adolescent or adult from a TB high-burden country is almost always due to TB infection, not BCG

• There is no need for a BCG-vaccinated person with a positive TST to be treated

• Persons with pos TST from TB high-burden countries are at high risk of developing active TB & should be treated

QuantiFERON-TB

• QuantiFERON-TB Gold test (QFT-G)

• QFT-G = blood assay for M. tuberculosis (BAMT) – Measures the patient’s immune system reaction to M.

tuberculosis – Must be processed < 12 hours – Interpretation of results influenced by the patient’s risk for

infection with M. tuberculosis – Alternative to TST

QuantiFERON-TB

• Measures interferon (IFN)-gamma released in blood when incubated overnight with reagents, including antigens for M. tuberculosis

• Lymphocytes from persons with LTBI react to proteins by releasing IFN-gamma

Treatment Active TB

• TB treatment regimens must contain multiple drugs which M. tuberculosis is susceptible

• Treating with a single drug can lead to resistance

• Adding a single drug to a failing regimen can lead to resistance

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QUESTIONS ?

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THE END